Correspondence

Correction

Histone Deacetylase Activity and COPD

N Engl J Med 2005; 353:528-529August 4, 2005

Article

To the Editor:

In their study, Ito and colleagues (May 12 issue)1 observed reductions in both the activity and expression of histone deacetylases (HDACs), especially HDAC2, in patients with chronic obstructive pulmonary disease (COPD). In addition, the activity inversely correlated with the severity of COPD.

Histone-modifying enzymes play essential roles in gene regulation.2 The balance between histone acetylation and deacetylation appears to be crucial to normal cell growth. Disruption of either of these molecular mechanisms has been associated with the development of cancer. Several molecules and genes have been identified or developed or both to inhibit HDACs.3 Valproic acid, an antiepileptic drug that has been commercially available for decades, has been found to inhibit HDACs, including HDAC2.4 However, there is no evidence that valproic acid worsens pulmonary function in patients taking the medicine.5 The “chicken-and-egg” conundrum remains unresolved: Does the reduction of HDAC activity cause severe COPD, or is it a secondary event?

Albert Y. Lin, M.D., M.P.H.
Santa Clara Valley Medical Center, San Jose, CA 95128
albert.lin@hhs.co.santa-clara.ca.us

5 References

1. 1

   Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352:1967-1976
   Full Text | Web of Science | Medline

2. 2

   Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999;98:285-294
   CrossRef | Web of Science | Medline

3. 3

   Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res 2004;91:137-168
   CrossRef | Web of Science | Medline

4. 4

   Kramer OH, Zhu P, Ostendorff HP, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 2003;22:3411-3420
   CrossRef | Web of Science | Medline

5. 5

   Physicians' desk reference. 58th ed. Montvale, N.J.: Thomson PDR, 2004.
   

To the Editor:

The following statement in the Discussion section of the article by Ito et al. is rather confusing: “In the present study, there was a positive correlation between HDAC activity and disease severity, as measured by the percent of predicted FEV₁ [forced expiratory volume in one second]. . . .” The Results section, Figure 1D, and the abstract clearly indicate that there was apparently a negative correlation between HDAC activity and disease severity. I assume that the authors meant to say that there was a positive correlation between HDAC activity and FEV₁.

Angshu Bhowmik, M.B., B.S.
Homerton University Hospital, London E9 6SR, United Kingdom

Author/Editor Response

Histone modification regulates many genes, including those involved in normal cell growth. Eleven classic HDACs have been identified.1 In patients with COPD, we found a marked reduction in HDAC2, with lesser reductions in HDAC5 and HDAC8. Different HDACs appear to be involved in different cellular functions and presumably regulate different sets of genes. Indeed, the targeted reduction of HDAC2 through RNA interference results in reduced responsiveness to corticosteroids in a human epithelial cell line (A549), whereas this reduction is not observed when other classic HDACs are inhibited.2 Valproate, a nonselective inhibitor of classic HDACs, is associated with 50 percent inhibition of HDAC activity at approximately 200 μg per milliliter (1.4 mmol per liter) in A549 cells. Steady-state plasma concentrations of valproate in patients with epilepsy are 50 to 100 μg per milliliter (0.3 to 0.7 mmol per liter), so it is possible that clinical doses may have some HDAC inhibitory effect, enhancing inflammation or reducing responsiveness to corticosteroids in patients with inflammatory diseases. There is one report of increased circulating proinflammatory cytokines in children with epilepsy treated with valproic acid.3 However, we are not aware that a worsening of inflammatory diseases has been investigated or reported with valproate. We agree with Dr. Lin that it is not certain whether the reduction in HDAC activity is a consequence or a cause of severe COPD, but we would like to suggest that it is both and that it provides a molecular basis for the increasing pulmonary inflammation as COPD progresses.

We agree with Dr. Bhowmik that the sentence in the Discussion was incorrectly written. We should have stated that there was a negative correlation between HDAC activity and disease severity.

Peter J. Barnes, D.M., D.Sc.
Ian M. Adcock, Ph.D.
Kazuhiro Ito, Ph.D.
Imperial College, London SW3 6LY, United Kingdom
p.j.barnes@imperial.ac.uk

3 References

1. 1

   de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737-749
   CrossRef | Web of Science | Medline

2. 2

   Ito K, Adcock IM, Barnes PJ. Knock out of histone deacetylase-2 by RNA interference enhances inflammatory gene expression and reduces glucocorticoid sensitivity in human epithelial cells. Am J Respir Crit Care Med 2004;169:A847-A847 abstract.
   

3. 3

   Verrotti A, Basciani F, Trotta D, Greco R, Morgese G, Chiarelli F. Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte chemoattractant protein-1. Clin Exp Med 2001;1:133-136
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Citing Articles (1)

Citing Articles

1. 1

   Ron S. Broide, Jeff M. Redwine, Najla Aftahi, Warren Young, Floyd E. Bloom, Christopher. J. Winrow. (2007) Distribution of histone deacetylases 1–11 in the rat brain. Journal of Molecular Neuroscience 31:1, 47-58
   CrossRef